MicroRNA-34 suppresses breast cancer invasion and metastasis by directly targeting Fra-1
MicroRNA-34 suppresses breast cancer invasion and metastasis by directly targeting Fra-1
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MicroRNA-34通过直接靶向Fra-1抑制乳腺癌侵袭和转移
DOI：
10.1038/onc.2012.432
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发表时间：
2013-09-05
期刊：
影响因子：
8
通讯作者：
Liu, Z.
中科院分区：
文献类型：
--
作者：
Yang, S.;Li, Y.;Liu, Z.
MicroRNAs在肿瘤转移中起关键作用。在这里，我们描述miR-34a和miR-34c(miR-34a/c)在乳腺癌转移中的调节和作用。表达分析证实miR-34a/c在转移性乳腺癌细胞和有淋巴结转移的人原发乳腺肿瘤中的表达显著降低。MiR-34a/c过表达在体外可抑制乳腺癌细胞的迁移和侵袭，在体内可抑制远处肺转移。进一步的研究发现，Fos相关抗原1(Fra-1或Fosl1)是miR-34a/c的下游靶点，因为miR-34a/c直接与Fra-1的3‘非翻译区结合，从而降低了Fra-1的mRNA和蛋白水平。Fra-1的沉默概括了miR-34a/c过表达的作用，而Fra-1的强表达逆转了miR-34a/c的抑制作用。此外，在转移性乳腺癌组织中miR-34a的显著下调与Fra-1的表达呈负相关。我们的结果表明miR-34a/c通过靶向Fra-1癌基因调控乳腺癌的转移和侵袭，提示miR-34在乳腺癌治疗中的应用。
MicroRNAs have key roles in tumor metastasis. Here, we describe the regulation and function of miR-34a and miR-34c (miR-34a/c) in breast cancer metastasis. Expression analysis verified that miR-34a/c expression is significantly decreased in metastatic breast cancer cells and human primary breast tumors with lymph node metastases. Overexpression of miR-34a/c could inhibit breast cancer cell migration and invasion in vitro and distal pulmonary metastasis in vivo. Further studies revealed that Fos-related antigen 1 (Fra-1 or Fosl1) is a downstream target of miR-34a/c as miR-34a/c bound directly to the 3′ untranslated region of Fra-1, subsequently reducing both the mRNA and protein levels of Fra-1. Silencing of Fra-1 recapitulated the effects of miR-34a/c overexpression, whereas enforced expression of Fra-1 reverses the suppressive effects of miR-34a/c. Moreover, significant downregulation of miR-34a in metastatic breast cancer tissues was found to be inversely correlated with Fra-1 expression. Our results demonstrate that miR-34a/c functions as a metastasis suppressor to regulate breast cancer migration and invasion through targeting Fra-1 oncogene and suggest a therapeutic application of miR-34 in breast cancer.